MOLECULAR EPIDEMIOLOGY AND BIOLOGICAL DETERMINANTS OF HTLV-1

点击翻译按钮获取中文摘要

The study of human T-cell leukemia/lymphotropic virus type I (HTLV-I) and simian T cell leukemia virus type I (STLV-I) molecular evolution is near completion. Further analysis of STLV-I from a few Asian monkey species and pygmy chimpanzees (which are closer to humans than Pan Troglodytes) will be performed. Studies of HTLV-I rabbit models have shifted from pathogenesis to vaccine because 1) rats and mice have been determined to be a more economical model for HTLV-I, and 2) partial success of NYVAC/ALVAC vaccine for protection against human immunodeficiency virus type 2 challenge (see Z01CP05688-03). Major emphasis has been on the functional role of a newly identified protein, p12(I), from the pX region of the HTLV-I genome, which is correlated genetically and functionally to the bovine, papillomavirus 1 (BPV-1) E5 oncoprotein. Further, this small protein, which is located in the golgi complex, binds to a resident protein of the golgi complex, the 16 kilodalton subunit of the proton H+ vacuolar ATPase. Increasing evidence suggests that some viral proteins (E5 of BPV, gp55 of spleen focus forming virus) might function by binding to growth factor receptors and mimic natural ligand function. The possible role of p12(I) in HTLV-l transformation of human T-cells has been investigated by testing its binding to the alpha- and beta-chains of the interleukin 2 (IL-2) receptor. The p12 binds specifically to the IL-2 beta-chain but not to the alpha-chain. We are presently mapping the protein domains involved in these interactions and in parallel trying to develop a transformation assay in hematopoietic cells. The second part of this project involves the development of an HTLV-I vaccine. NYVAC and ALVAC HTLV-I constructs (for background information see Z01CP05688-03) expressing the HTLV-I envelope were used to immunize rabbits. Testing of the immunoresponse against these constructs in the immunized animals with parallel analysis on the natural immunoresponse in humans is ongoing.